Transcription Factor CHOP

About: Transcription Factor CHOP is a research topic. Over the lifetime, 443 publications have been published within this topic receiving 46408 citations.

REV-ERBα Activates C/EBP Homologous Protein to Control Small Heterodimer Partner–Mediated Oscillation of Alcoholic Fatty Liver

Abstract: The small heterodimer partner (SHP) nuclear receptor is an important regulator of nonalcoholic fatty liver disease. However, little is known about the role of SHP in alcoholic fatty liver. In this study, we used a modified chronic ethanol-binge model to examine cyclic alterations of lipid metabolism in wild-type (WT) and Shp-/- mice over a 24-hour period after binge. The serum and hepatic lipid profiles, as well as the expression of lipid synthesis genes and markers of endoplasmic reticulum stress, exhibited distinct variations in WT and Shp-/- mice in response to ethanol diet plus ethanol binge (ED+E) and control diet plus maltose binge. ED+E induced steatosis in WT mice, which correlated with a marked up-regulation of activating transcription factor 4 protein (ATF4) but down-regulation of C/EBP homologous protein (CHOP) and sterol regulatory element-binding transcription factor 1c protein (SREBP-1c). On the contrary, the control diet plus maltose binge caused lipid accumulation in Shp-/- mice, which was accompanied by a sharp elevation of CHOP, SREBP-1c, and REV-ERBα proteins but a diminished ATF4. REV-ERBα activated CHOP promoter activity and gene transcription, which were inhibited by SHP. Knockdown Rev-Erbα in Shp-/- mice prevented steatosis induced by ED+E. Our study revealed a critical role of SHP and REV-ERBα in controlling rhythmic CHOP expression in alcoholic fatty liver.

Comparable transforming capacities and differential gene expression patterns of variant FUS/CHOP fusion transcripts derived from soft tissue liposarcomas

Abstract: The chromosomal translocation t(12;16)(q13;p11) is a common genetic alteration in myxoid and round-cell liposarcomas It results in transcription of various chimeric FUS/CHOP fusion transcripts that encode different oncogenic proteins Recent reports suggest that these may have different neoplastic transformation activities To audit this hypothesis, we transfected expression plasmids for the two major variant FUS/CHOP transcripts I and II in NIH 3T3 cells and determined the number of outgrowing foci as well as their growth potential in soft agar In addition, we compared tumour growth in nude mice upon subcutaneous injection of the respective transfectants No significant differences in transformation assays in vitro and in vivo were observed, suggesting that both variant transcripts confer comparable transforming activities The histopathological picture of tumours derived from both cell populations resembles high-grade spindle cell sarcomas This suggests that both FUS/CHOP variants cause similar patterns of differential gene expression This hypothesis was confirmed by mRNA-expression profiles of the respective cell clones Strong overexpression of the pentaxin-related gene (PTX), the osteoblast-specific factor 2 (osf-2), the basic Kruppel-like factor (bklf), the leucoprotease inhibitor, and the cyclophilin B were observed in both types of FUS/CHOP-transfected cell clones Taken together, our data suggest that different FUS/CHOP variants cause transformation of mesenchymal cells via the same pathways with comparable efficacy

Regulation and role of the ER stress transcription factor CHOP in alveolar epithelial type-II cells.

Abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by type-II alveolar epithelial cell (AECII) injury and fibroblast hyperproliferation. Severe AECII endoplasmic reticulum (ER) stress is thought to underlie IPF, but is yet incompletely understood. We studied the regulation of C/EBP homologous protein (CHOP), a proapoptotic ER-stress-related transcription factor (TF) in AECII-like cells. Interestingly, single or combined overexpression of the active ER stress transducers activating transcription factor-4 (Atf4) and activating transcription factor-6 (p50Atf6) or spliced x-box-binding protein-1 (sXbp1) in MLE12 cells did not result in a substantial Chop induction, as compared to the ER stress inducer thapsigargin. Employing reporter gene assays of distinct CHOP promoter fragments, we could identify that, next to the conventional amino acid (AARE) and ER stress response elements (ERSE) within the CHOP promoter, activator protein-1 (AP-1) and c-Ets-1 TF binding sites are necessary for CHOP induction. Serial deletion and mutation analyses revealed that both AP-1 and c-Ets-1 motifs act in concert to induce CHOP expression. In agreement, CHOP promoter activity was greatly enhanced upon combined versus single overexpression of AP-1 and c-Ets-1. Moreover, combined overexpression of AP-1 and c-Ets-1 in MLE12 cells alone in the absence of any other ER stress inducer was sufficient to induce Chop protein expression. Further, AP-1 and c-Ets-1 were upregulated in AECII under ER stress conditions and in human IPF. Finally, Chop overexpression in vitro resulted in AECII apoptosis, lung fibroblast proliferation, and collagen-I production. We propose that CHOP activation by AP-1 and c-Ets-1 plays a key role in AECII maladaptive ER stress responses and consecutive fibrosis, offering new therapeutic prospects in IPF. KEY MESSAGES: Overexpression of active ER stress sensors Atf4, Atf6, and Xbp1 does not induce Chop. AP-1 and c-Ets-1 TFs are necessary for induction of the ER stress factor Chop. AP-1 and c-Ets-1 alone induce Chop expression in the absence of any ER stress inducers. AP-1 and c-Ets-1 are induced in AECII under ER stress conditions and in human IPF. Chop expression alone triggers AECII apoptosis and consecutive profibrotic responses.

Combined chemical–genetic approach identifies cytosolic HSP70 dependence in rhabdomyosarcoma

Abstract: Cytosolic and organelle-based heat-shock protein (HSP) chaperones ensure proper folding and function of nascent and injured polypeptides to support cell growth. Under conditions of cellular stress, including oncogenic transformation, proteostasis components maintain homeostasis and prevent apoptosis. Although this cancer-relevant function has provided a rationale for therapeutically targeting proteostasis regulators (e.g., HSP90), cancer-subtype dependencies upon particular proteostasis components are relatively undefined. Here, we show that human rhabdomyosarcoma (RMS) cells, but not several other cancer cell types, depend upon heat-shock protein 70 kDA (HSP70) for survival. HSP70-targeted therapy (but not chemotherapeutic agents) promoted apoptosis in RMS cells by triggering an unfolded protein response (UPR) that induced PRKR-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor α (eIF2α)-CEBP homologous protein (CHOP) signaling and CHOP-mediated cell death. Intriguingly, inhibition of only cytosolic HSP70 induced the UPR, suggesting that the essential activity of HSP70 in RMS cells lies at the endoplasmic reticulum-cytosol interface. We also found that increased CHOP mRNA in clinical specimens was a biomarker for poor outcomes in chemotherapy-treated RMS patients. The data suggest that, like human epidermal growth factor receptor 2 (HER2) amplification in breast cancer, increased CHOP in RMS is a biomarker of decreased response to chemotherapy but enhanced response to targeted therapy. Our findings identify the cytosolic HSP70-UPR axis as an unexpected regulator of RMS pathogenesis, revealing HSP70-targeted therapy as a promising strategy to engage CHOP-mediated apoptosis and improve RMS treatment. Our study highlights the utility of dissecting cancer subtype-specific dependencies on proteostasis networks to uncover unanticipated cancer vulnerabilities.